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ON-TIME-2 On going- T irofiban I n M yocardial Infarction E valuation 1 Year Follow-Up

ON-TIME-2 On going- T irofiban I n M yocardial Infarction E valuation 1 Year Follow-Up. Conflicts of interest. Speaker’s name: Christian W. Hamm I have the following potential conflicts of interest to report: Consulting & speaker honoraria: GSK, Sanofi-Aventis, The Med. Comp.,

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ON-TIME-2 On going- T irofiban I n M yocardial Infarction E valuation 1 Year Follow-Up

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  1. ON-TIME-2Ongoing-Tirofiban In MyocardialInfarction Evaluation1 Year Follow-Up

  2. Conflicts of interest Speaker’s name: Christian W. Hamm I have the following potential conflicts of interest to report: Consulting & speaker honoraria: GSK, Sanofi-Aventis, The Med. Comp., Merck, Lilly, Iroko, Pfizer, Boehringer Ingelheim

  3. Trial Design(Registration: ISRCTN 06195297) Multicenter, prospective, randomized, international Analysis: ITT End-points adjudicated (CEC) Investigator initiated and driven Unrestricted grant from Merck and Iroko

  4. Trial Leadership Co-Principle Investigators Arnoud van t´Hof Christian W. Hamm Jurriën M. ten Berg Steering Committee P. Stella L. van den Merckhoff T. Dill (Germany, MRI) G. Giannitsis (biomarker) J. Brachmann S. Guptha CRO Diagram B.V., J. Klijn

  5. Open Label June 2004 – June 2006 N=414 2 centres Netherlands HBD Tirofiban or no Tirofiban 600 mg Clopidogrel, heparine, ASA Double Blind June 2006 – Nov 2007 N=984 24 centres Netherlands, Germany, Belgium HBD Tirofiban or Placebo 600 mg Clopidogrel, heparine, ASA Study Phases

  6. Inclusion criteria • Chest pain > 30 min but less than 24 hours • ST  in 2 contiguous leads: > 0.2 mV (anterior MI) or 0.1 mV (non-anterior MI) • Exclusion criteria • Age > 85 yrs • Women < 50 yrs • Lytic therapy < 24 hrs • Acenocoumarol < 7 days • C.I to 2b/3a blockade • Killip IV • Hemodialysis

  7. Acute myocardial infarction diagnosed in ambulance or referral center ASA+600 mg Clopidogrel Placebo Tirofiban * Transportation PCI centre Angiogram Angiogram Tirofiban provisional Tirofiban cont’d PCI *Bolus: 25 µg/kg & 0.15 µg/kg/min infusion

  8. Endpoints • Primary • Residual ST segment deviation (>3mm) 1 hour after PCI • Key Clinical Secondary • Combined occurrence of death, recurrent MI, urgent TVR or thrombotic bailout at 30 days follow-up • Safety ( major bleeding) • Death at 1 year follow-up

  9. Baseline Data • Open Label Double Blind • (n=414) (n=984) • Age (mean, yr) 62 62 • Male gender (%) 77 76 • Prev MI (%) 11 9 • Diabetes (%) 11 12 • Hypertension (%) 34 34 • Smoking (%) 48 47 • Anterior MI (%) 45 42 • Killip > 1 (%) 13 12 • Ambulance RX (%) 98 95

  10. Ischemic Time

  11. ON-TIME 2The Lancet 2008; 372: 537-46

  12. Residual ST Deviation after PCI

  13. All-Cause Mortality 30 Days open label & double-blind, n = 1398

  14. All-Cause Mortality 1-Year open label & double-blind, n = 1398 P = 0.077

  15. All cause Mortality 1 Year Double Blind Open Label N=984 N=414 -37% -36% RR: 0.78 (95% CI: 0.53-1.14, p=0.157) RR: 0.77 (95% CI: 0.46-1.29, p=0.276)

  16. All cause Mortality and AMI 1 Year Double Blind Open Label N=984 N=414 -41% -19%

  17. 1 Year Survival: Patients with Primary PCI open label & double-blind, n = 1.155 P = 0.007

  18. Summary: HD Tirofiban in the Ambulance • Strong trend to reduced mortality continues over 1 year follow-up in open label and double blind cohorts. • In patients undergoing primary PCI (84%) mortality is significantly lower. • Highest efficacy in elderly (> 65 yrs), in Killip class  2 and in early presenters.

  19. Conclusion • Prehospital HD Tirofiban: • A Promising Option for AMI Networks

  20. Thank You !

  21. 1 Year Survival: Patients with Primary PCI double-blind, n = 826

  22. All-Cause Mortality 1-Year double-blind, n = 984

  23. 1-Year Cardiac Mortality double-blind, n = 984

  24. ‘further platelet aggregation inhibition besides high-dose clopidogrel improves ST resolution both before and after PCI’ On-TIME 2 study, Lancet 2008;372:537-46 Double Blind Phase

  25. Initial TIMI flow

  26. Pooled AnalysisOpen Label and Double Blind • N=1398 Tirofiban Placebo P-value (n=709) (n=689) • Age (mean, yr) 62 62 NS • Male gender (%) 77 76 NS • Prev MI (%) 9 9 NS • Diabetes (%) 12 11 NS • Hypertension (%) 34 34 NS • Smoking (%) 46 49 NS • Anterior MI (%) 43 43 NS • Killip > 1 (%) 11 14 NS • Ambulance triage (%) 96 97 NS

  27. Pooled AnalysisResidual ST deviation Plac/no Tiro N=689 Tirofiban N=709 mean ± SD p- value 14.6 ± 9.1 Baseline ST-deviation (mm) 14.2 ± 8.6 0.645 Residual ST-deviation 4.8 ± 6.04 3.7 ± 5.2 0.001 1 hr post PCI (mm) normal ECG 1 hr post PCI 30.0% 36.1% 0.003 > 3 mm ST-deviation 45.0% 38.7% 0.024

  28. Effect on different End Points Surrogate End Points Clinical End Points

  29. Survival free from MACE

  30. Residual ST-Deviation and Mortality

  31. Pain-diagnosis<75 min Pain-diagnosis>75 min Why in ambulance? Surrogate End Points

  32. Pain-diagnosis>75 min Why in ambulance? Pain-diagnosis<75 min

  33. The Netherlands: 1. Isala klinieken Zwolle Dr. A.W.J. van ’t Hof 2. Antonius Ziekenhuis Nieuwegein Dr. J. ten Berg 3. UMC Utrecht Drs. P.R. Stella 4. Medisch Spectrum Twente Dr. K. van Houwelingen Germany: 1. Kerckhoff-Klinik Prof. Dr. C. Hamm 2. Universitätsklinikum Heidelberg Prof. Dr. H Katus 3. St. Johannes HospitalDortmund Prof. Dr. Heuer 4. Klinikum Coburg Prof. Dr. J. Brachmann 5. KlinikumLüdenscheid Dr. Lemke 6. SegebergerKliniken Prof. Dr. G. Richardt 7. PhilippsUniversität Marburg Prof. Maisch 8. AllgemeinesKrankenhausCelle Prof. Dr. W. Terres 9. Uni-klinikGiessen Prof. Dr. H. Tillmanns 10. ImtalklinikPfaffenhofen Prof. C. Firschke 11. Med. Hochschule Hannover Prof. Dr. Schieffer 12. UniklinikMannheim Dr. T. Süselbeck 13. UniklinikLübeck Prof. Dr. H. Schunkert 14. StätischesKlinikumLüneburg Prof. Dr. W. Kupper 15. ZentralklinikumSuhl Prof. W. Haberbosch 16. Uni-KlinikRostock Prof. Dr. C.Nienaber 17. KreiskrankenhausBergstrasse Dr. W. Auch-Schwelk 18. AsklepiosKlinik St. Georg Prof. Dr. K.H. Kuck 19. KlinikumDarmstadt Prof Dr. G. Werner 20. EvangelischesKrankenhausHolzminden Dr. C. Beythien Belgium: 1. AZ Sint-Jan AV Brugge Dr. P. Coussement Participating Centers

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